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Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling

Abstract

Natural killer T cells, which are stimulated by lipids presented by CD1d molecules, are crucial in antiviral host defense. How viruses evade natural killer T cell recognition remains unclear. Here we show that infection with herpes simplex virus type 1 (HSV-1) reduced CD1d surface expression on antigen-presenting cells. HSV-1 did not inhibit CD1d protein synthesis or enhance constitutive CD1d endocytosis. Instead, HSV-1 prevented the reappearance of endocytosed CD1d on the cell surface by redistributing endocytosed CD1d to the lysosome limiting membrane. HSV-1 might also inhibit the transport of newly synthesized CD1d to the cell surface. Such inhibition of CD1d surface expression impaired antigen-presenting cell–mediated stimulation of natural killer T cells, supporting the idea that this mechanism may be an important HSV-1 immune evasion strategy.

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Figure 1: HSV-1 downregulates surface CD1d in antigen-presenting cells.
Figure 2: Inhibition of protein synthesis is not responsible for HSV-1-mediated downregulation of surface CD1d expression.
Figure 3: HSV-1-mediated downregulation of surface CD1d expression inhibits NKT cell activation.
Figure 4: Biogenesis and surface arrival of CD1d in HSV-1 infected cells.
Figure 5: Recycling of CD1d to the cell surface is impaired in HSV-1-infected cells.
Figure 6: CD1d is trapped in internal vesicles after HSV-1 infection.

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Acknowledgements

We thank A. Iwasaki, R. Medzhitov, P. Lehner, A. Chow and D.R. Peaper for discussions, and M. Pypaert (Yale Cell Biology Imaging Facility, New Haven, Connecticut) for the immuno-electron microscopic analysis. Supported by the National Institutes of Health (AI059167 to P.C.), Howard Hughes Medical Institute (P.C.) and Cancer Research Institute (W.Y.).

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W.Y. and A.D. did the experiments; P.C. supervised the work.

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Correspondence to Peter Cresswell.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CD1d is relocalized from internal vesicles to the limiting membrane of multivesicular bodies after HSV-1 infection. (PDF 10714 kb)

Supplementary Video 1

Three-dimensional reconstruction of an infected Hela.CD1d.eGFP cell (24 h after infection with vhs-deficient HSV-1). (MPG 1804 kb)

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Yuan, W., Dasgupta, A. & Cresswell, P. Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol 7, 835–842 (2006). https://doi.org/10.1038/ni1364

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